Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States. The unusually low survival rate of pancreatic cancer is due to the aggressively invasive and metastatic nature of these tumors, and their resistance to currently used chemical and radiotherapies. The INK4A/ARF locus is inactivated in 80-95% of sporadic PDAC. Synchronous p53 mutations occur in 40% of cases with INK4A/ARF inactivation, suggesting that these tumor suppressors may have non-overlapping functions in pancreatic cancer suppression. Mounting evidence suggests that the ARF tumor suppressor, which activates p53 in response to oncogenic stress, also possesses p53-independent functions relevant to the suppression of invasion and metastasis. ARF inhibits invasion and migration in lung and colon cancer cell lines, and ARF-null tumors exhibit increased aggressiveness in a mouse model of hepatocellular carcinoma. These p53-independent activities of ARF can be explained, in part, by its ability to bind and antagonize the corepressor C-terminal Binding Protein (CtBP) and downregulate the phosphatidylinositol-3 (PI3)-kinase pathway via derepression of PTEN expression. Therefore, understanding the biologic function of ARF/CtBP complexes and their potential contribution to pancreatic tumor progression and metastasis may provide critical insights that could lead to novel therapeutics. In this proposal, we will systematically analyze the molecular actions of ARF and CtBP specific to regulation of the PI3-kinase pathway and pancreatic oncogenesis in vitro and in a murine transgenic PDAC model. A small molecule inhibitor of CtBP will be tested in the murine PDAC model that may lead to the development of a new class of targeted therapeutics in pancreatic cancer. Such therapeutics might also be of great utility in the many other human cancers where CtBP is deregulated due to ARF inactivation. PUBLIC HEALTH RELEVANCE: Pancreatic cancers, which are among the deadliest of human cancers, often lose the function of a key tumor suppressor protein called ARF. As a result of ARF's absence, a cancer promoting protein termed C-terminal Binding Protein (CtBP) is activated, causing cancer cells to migrate more rapidly, become more invasive, and survive more easily in hostile environments or when exposed to cancer therapeutics. A drug called MTOB that blocks the action of CtBP and can immobilize and kill cancer cells in a culture dish will be tested for its effect in mice that develop pancreatic cancer, as a prelude to future testing of this or related drugs in patients afflicted with this deadly form of cancer.